Listening to Spravato & Psychedelic Policy Updates
Listening to Spravato & Psychedelic Policy Updates
When we think about the future of psychedelics, there are three general categories of legal access on the horizon—medical, legalization, and decriminalization.
But overlaps or hybrids between categories are emerging, and the details are rich fodder for analysis of the kind I enjoy.
As we’ll look at today, a recent bill in Maryland is an example of a medical/legalization1 hybrid. It seeks to simultaneously fund psychedelic research and offer cost-free treatment for veterans and first responders. This is an example of the apparent interest states have in filling the gaps left by the absence of federal research funding for psychedelics.
As an interesting, albeit unrelated, juxtaposition, we have the recent decision by the UK’s National Institute for Health and Care Excellence to NOT recommend Spravato/Esketamine for Treatment-Resistant Depression in the country’s National Health Service because of insufficient evidence, safety concerns, and costs.
In these examples, we have one government body sponsoring research and cost-free treatment of promising but not yet approved therapies. But on the other hand, we have a government body rejecting the use and reimbursement for an already approved drug in a similar category.
Let’s see if we can make some sense of this.
Listening to Spravato
The UK Rejects Spravato… Again
In the UK, the National Institute for Health and Care Excellence (NICE), the organization that publishes treatment guidelines for the National Health Service (NHS), has again decided against recommending Spravato2 for Treatment-Resistant Depression.
From the Final Appraisal Determination Document:
“Esketamine nasal spray with a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI) is not recommended…
The clinical trial evidence suggests that for people who have had at least 3 antidepressants with or without another treatment, esketamine with an SSRI or SNRI could be more effective than placebo with an SSRI or SNRI. But this is very uncertain, because this evidence only considers a small number of people from the full trial population. The long-term effects of esketamine are also uncertain because the trials were short.
Also, the trial evidence excluded people with characteristics of depression like psychosis or suicidal ideation with intent. This limits how well the evidence applies to the NHS…
The limitations in the clinical evidence and economic model mean it is not possible to determine a reliable cost-effectiveness estimate. Esketamine is unlikely to be an acceptable use of NHS resources, so it is not recommended. Further research is recommended to address some of the uncertainties.”
Mark Horowitz, a psychiatrist/Ph.D. in training at UCL—and co-author of Esketamine: uncertain safety and efficacy data in depression—offered an extensive summary of the decision in this tweet thread:
This is the third time NICE has rejected Spravato for use in the NHS and is indicative of Spravato’s broader commercialization rollout.
From the beginning, independent researchers voiced concerns about the data from clinical trials. For further reading on the safety and efficacy of Spravato, see the following:
Are we repeating mistakes of the past? A review of the evidence for
Esketamine for treatment-resistant depression: seven concerns about efficacy and FDA approval
FDA vs NICE/NHS on Spravato
One of the more confusing aspects of this Spravato saga is the different messaging from the FDA in the US compared to the NICE/NHS in the UK.
As we just noted, NICE points out significant limitations of clinical trial results and concerning safety data. As a result, it refuses to deploy Spravato in the country’s healthcare system.
On the other hand, in the US, the FDA recently went in the opposite direction by encouraging the use of the FDA-approved Spravato in warning clinicians against the use of intranasal racemic ketamine from compounding pharmacies:
“The benefit and risk profile for Spravato (esketamine) has been established, as described in the FDA-approved labeling and the approved Spravato REMS program, with elements to assure safe use. However, the benefit and risk profile for compounded ketamine nasal spray has not been evaluated.”
But here’s where it gets weird—the FDA’s warning against racemic intranasal ketamine is based on data from the FDA Adverse Event Reporting System (FAERS)
“that identified five cases, reported between 2016-2021, associated with psychiatric events such as delusion, dissociation, visual hallucination, and panic attack as well as abuse and misuse following the use of compounded ketamine nasal spray.”
Compare this to at least two salient data points:
This is the same regulatory agency that approved Spravato, which had three suicides in the active treatment group in clinical trials compared to zero in the placebo group3.
In a study titled Post-Marketing Safety Concerns with Esketamine: A Disproportionality Analysis of Spontaneous Reports Submitted to the FDA Adverse Event Reporting System, a search of that same FAERS database between March 2019-March 2020 “contained 962 cases of esketamine-related AEs, with signals detected for several AEs, such as dissociation, sedation, feeling drunk, suicidal ideation, and completed suicide.”
Weird, right?
The FDA put out a warning to clinicians about a drug that had five cases of panic attacks, hallucinations, and abuse over a five-year period and in the next paragraph directs them to instead use a product that has *checks notes* NINE HUNDRED AND SIXTY-TWO reported cases which included actual completed suicides. (It was actually “2,274 esketamine-related AEs in 962 patients (mean 2.4 AEs per person); 389 suffered from serious AEs, including 22 deaths.”)4
Am I missing something?
Is this the right way to frame it?
I understand it is normal for new drugs to have adverse events reported after the approval, but doesn’t this seem extreme?
Is this just the inherent difficulty of understanding and treating severe cases of treatment-resistant depression? The authors of the ‘Post-Marketing’ paper offer a fitting parting note on this topic:
“A fourth major finding of our analysis refers to the high reporting ratios of suicidal ideation, which could be considered a common symptom in TRD and completed suicide. Therefore, it can be very difficult to distinguish between suicidal ideation as part of the depressive illness from suicidal ideation related to lack of esketamine efficacy, or suicidal ideation as a reaction induced by esketamine [38]. Safety signals for suicidal and self-injurious ideation, but not for completed suicide and suicide attempt, remained after comparing esketamine with venlafaxine. This result might imply that clinical features of TRD may contribute to the risk of completed/attempted suicide. However, the relative risk of reporting suicidal ideation was 24-fold higher than for other drugs and 5–9 times higher than venlafaxine, which means an extremely serious concern that cannot be ignored, especially in males as the disproportionality was stronger.”
Maryland’s Psychedelic Policy Update
From Marijuana Moment:
“The governor of Maryland announced on Friday that he will allow a bill to create a state fund to provide “cost-free” access to psychedelics like psilocybin, MDMA and ketamine for military veterans suffering from post-traumatic stress disorder (PTSD) and traumatic brain injury to take effect without his signature…
The psychedelics bill, meanwhile, will establish what’s being called the Post-Traumatic Stress Disorder and Traumatic Brain Injury Alternative Therapies Fund. It stipulates that money from that fund must be used to study “the use of alternative therapies for veterans with PTSD and traumatic brain injuries.”
This approach fits into the East Coast vs. West Coast style of policies I laid out a few weeks ago:
“…the Connecticut approach is a practical counterbalance to the pioneering legalization paths underway on the West Coast, with Oregon's Measure 109, California's Bill 519, and Colorado's Natural Medicine Health Act.
We might even say two distinct approaches to state-level psychedelic policy reform are emerging along the stereotypical East Coast—West Coast dichotomy that has characterized the differences between cultural, business, and power centers of the respective coasts…
My thinking here is that two general categories of psychedelic policy are forming.
On the one hand, ‘West Coast’ psychedelic policy reform will look more like cannabis reform efforts by creating adult-use frameworks. On the other hand, the ‘East Coast’ model states will establish budgets for state-funded research and treatment programs.
Another way to think about it is that East Coast-style research and access programs are a way to fill the gap left by the absence of federal science funding.
This combination of research and access, enabled by state funds, is exciting and could create the rails for future commercialization and/or legalization. Again from a few weeks ago:
Critical features of commercialization include provider education (marketing) and reimbursement (insurance coverage).
But there are several considerations for psychedelic-assisted therapies, including:
Status as scheduled substances
Limitations of Risk Evaluation and Mitigation Strategies (REMS)
To-be determined aspects of the Drug-Labeling
Clinical infrastructure, therapist and provider training, and certifications
and the long duration of treatments
All of which would seem to make the early phases of commercialization extremely challenging.
Therefore, if states, which stand to benefit from improvements in mental health treatment, take on the cost and burden of establishing clinical and administrative infrastructure, they could help streamline the process.
I am looking forward to seeing how these programs develop.
Further Reading
Ceruvia Lifesciences to Supply LSD to Qualified Researchers at No Cost
From the Press Release:
“Ceruvia Lifesciences is pleased to announce that it has produced the world’s first LSD that meets stringent “Current Good Manufacturing Practices” (CGMP) standards required by the U.S. Food and Drug Administration for new drug approvals and is offering to supply it at no cost to qualified researchers. Ensuring the availability of a supply of CGMP LSD will be a key factor in advancing research into LSD’s safety and efficacy for the treatment of a range of neurological, mental health and neurodevelopmental disorders, including cluster headaches, migraines, alcohol use disorder, opioid use disorder, anxiety disorder and attention deficit disorder.”
The Guardian: Psychedelic House of Davos
“Often the world of psychedelic science finds itself in a catch-22 triangle of needing more research before politicians will change drug laws, yet needing more funding to do the necessary research, while investors need the laws to change before they will risk funding the research. Still, a handful of recent developments have kept this momentum alive.”
CBC: Small-scale possession of illicit drugs will be decriminalized in B.C. starting next year
“The federal government says Canadians 18 years of age and older will be able to possess up to a cumulative 2.5 grams of opioids, cocaine, methamphetamine and MDMA within British Columbia. The announcement is in response to a request from the province for an exemption from the law criminalizing drug possession.
This first-of-its-kind exemption will go into effect on Jan. 31, 2023, and last until Jan. 31, 2026, unless it is revoked or replaced before then. The exemption means there will be no arrests, charges or seizures for personal possession at or below the 2.5 gram threshold.”
Thanks for reading, have a great weekend!
Zach
“Legalization” is the wrong term since it enables access for a narrow patient population, but I am unsure what phrase to use here. Suggestions welcome.
Spravato is the trade name for Esketamine (one of two enantiomers of ketamine) developed by Janssen for Treatment-Resistant Depression. It received FDA approval in March 2019 (and EMA approval in December 2019); thus, it is the first FDA-approved “psychedelic-like” drug.
From A Word to the Wise About Intranasal Esketamine: “What is more worrisome than this rapid relapse coming off even less frequent esketamine administration were the three suicides that occurred 4–20 days after the last dose of esketamine (there were none in the placebo group). Two of the patients who died by suicide showed no previous signs of suicidal activity during the study, either at baseline or at the last visit. This suggests a protracted withdrawal reaction, as has been reported with opioids, and one that is different from the more physical withdrawal symptoms seen acutely with opioids”
This is further muddied by doing an actual FAERS search in real-time for ketamine and Spravato. Both have more AEs than the above data suggests, but Spravato has almost sixfold as many as ketamine.
